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Natural‐Product‐Inspired Aminoepoxybenzoquinones Kill Members of the Gram‐Negative Pathogen Salmonella by Attenuating Cellular Stress Response
Author(s) -
Mandl Franziska A.,
Kirsch Volker C.,
Ugur Ilke,
Kunold Elena,
Vomacka Jan,
Fetzer Christian,
Schneider Sabine,
Richter Klaus,
Fuchs Thilo M.,
Antes Iris,
Sieber Stephan A.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201607338
Subject(s) - natural product , bacteria , salmonella , antibacterial activity , gram negative bacteria , pathogenic bacteria , bacterial cell structure , microbiology and biotechnology , antibiotics , bacterial outer membrane , pathogen , biology , gram positive bacteria , chemistry , biochemistry , escherichia coli , gene , genetics
Gram‐negative bacteria represent a challenging task for antibacterial drug discovery owing to their impermeable cell membrane and restricted uptake of small molecules. We herein describe the synthesis of natural‐product‐derived epoxycyclohexenones and explore their antibiotic activity against several pathogenic bacteria. A compound with activity against Salmonella Typhimurium was identified, and the target enzymes were unraveled by quantitative chemical proteomics. Importantly, two protein hits were linked to bacterial stress response, and corresponding assays revealed an elevated susceptibility to reactive oxygen species upon compound treatment. The consolidated inhibition of these targets provides a rationale for antibacterial activity and highlights epoxycyclohexenones as natural product scaffolds with suitable properties for killing Gram‐negative Salmonella.